Biochemical Genetics

, Volume 52, Issue 9–10, pp 387–402 | Cite as

Association Between IL-10 Gene Promoter Polymorphism and Hepatitis B Viral Infection in an Egyptian Population

  • Roba M. Talaat
  • Mahmoud F. Dondeti
  • Soha Z. El-Shenawy
  • Omaima A. Khamiss


Cytokines play critical roles in the pathogenesis of hepatitis B virus infection (HBV). This work was designed to study the effect of IL-10 gene polymorphisms (−1082G/A and −819C/T) on susceptibility of Egyptians to HBV. Genotyping was performed using single-stranded polymorphism-polymerase chain reaction in 118 Egyptian hepatitis B patients and 119 healthy controls, and IL-10 serum levels were measured using ELISA. The frequency of IL-10 −1082G/G was significantly higher in HBV patients than in healthy controls, and G/A and A/A were not significantly different between groups. The distribution of IL-10 −819 genotypes was not significantly different between the HBV and healthy control groups. Although AT was significantly different between controls and patients, the distribution of the other haplotypes was not. IL-10 levels were significantly lower among hepatitis B patients. Our data stress the importance of IL-10 gene polymorphism in HBV infection. Depending on our preliminary work, IL-10 −1082G/G may act as a host genetic factor in the susceptibility to HBV infection in Egyptians.


IL-10 Hepatitis B Egyptians 



This work is part of a grant from the Egyptian Academy of Scientific Research and Technology (ASRT), Cairo, Egypt. The sponsors did not participate in the study design, in the collection, analysis, and interpretation of data, in the manuscript drafting, and in the decision to submit the article for publication.


  1. Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM (2000) Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology 31(6):1371–1373PubMedCrossRefGoogle Scholar
  2. Almarri A, Batchelor JR (1994) HLA and hepatitis B infection. Lancet 344(8931):1194–1195PubMedCrossRefGoogle Scholar
  3. Bataller R, North KE, Brenner DA (2003) Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 37(3):493–503PubMedCrossRefGoogle Scholar
  4. Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T (2003) Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol 98(1):144–150PubMedCrossRefGoogle Scholar
  5. Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S (1999) Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 1(1):3–19PubMedCrossRefGoogle Scholar
  6. Bozkaya H, Bozdayi M, Turkyilmaz R, Sarioglu M, Cetinkaya H, Cinar K, Kose K, Yurdaydin C, Uzunalimoglu O (2000) Circulating IL-2, IL-10 and TNF-alpha in chronic hepatitis B: their relations to HBeAg status and the activity of liver disease. Hepatogastroenterology 47(36):1675–1679PubMedGoogle Scholar
  7. Cacciarelli TV, Martinez OM, Gish RG, Villanueva JC, Krams SM (1996) Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and post-treatment with interferon alpha. Hepatology 24(1):6–9PubMedCrossRefGoogle Scholar
  8. Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, Donaldson PT (1999) Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 30(4):851–856PubMedCrossRefGoogle Scholar
  9. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P (1999) Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 42(6):1101–1108PubMedCrossRefGoogle Scholar
  10. Dienstag JL (2008) Hepatitis B virus infection. N Engl J Med 359(14):1486–1500PubMedCrossRefGoogle Scholar
  11. Dorman SE, Holland SM (2000) Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 11(4):321–333PubMedCrossRefGoogle Scholar
  12. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE (1999) Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 30(2):526–530PubMedCrossRefGoogle Scholar
  13. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW (1998) Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 95(16):9465–9470PubMedCrossRefPubMedCentralGoogle Scholar
  14. Eskdale J, Keijsers V, Huizinga T, Gallagher G (1999) Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1(2):151–155PubMedCrossRefGoogle Scholar
  15. Fattovich G (2003) Natural history and prognosis of hepatitis B. Semin Liver Dis 23(1):47–58PubMedCrossRefGoogle Scholar
  16. Fiorentino DF, Bond MW, Mosmann TR (1989) Two types of mouse T helper cell IV: Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170(6):2081–2095PubMedCrossRefGoogle Scholar
  17. Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, O’Garra A (1991) IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol 146(10):3444–3451PubMedGoogle Scholar
  18. Ganem D, Prince AM (2004) Mechanisms of disease: hepatitis B virus infection- natural history and clinical consequences. N Engl J Med 350(11):1118–1129PubMedCrossRefGoogle Scholar
  19. Gao QJ, Liu DW, Zhang SY, Jia M, Wang LM, Wu LH, Wang SY, Tong LX (2009) Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 15(44):5610–5619PubMedCrossRefPubMedCentralGoogle Scholar
  20. Guidotti LG, Chisari FV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65–91PubMedCrossRefGoogle Scholar
  21. Guidotti LG, Guilhot S, Chisari FV (1994) Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and independent pathways. J Virol 68(3):1265–1270PubMedPubMedCentralGoogle Scholar
  22. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV (1996) Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4(1):25–36PubMedCrossRefGoogle Scholar
  23. Haukim N, Bidwell JL, Smith AJ, Keen LJ, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hard C, D’Alfonso S (2002) Cytokine gene polymorphism in human disease: on-line databases, suppl. 2. Genes Immun 3(6):313–330PubMedCrossRefGoogle Scholar
  24. Höhler T, Gerken G, Notghi A, Lubjuhn R, Taheri H, Protzer U, Lohr HF, Schneider PM, Meyer zum Büschenfelde KH, Rittner C (1997) HLA-DRB1*1301 and *1302 protect against chronic hepatitis B. J Hepatol 26(3):503–507PubMedCrossRefGoogle Scholar
  25. Höhler T, Kruger A, Gerken G, Schneider PM, Meyer zum Büschenefelde KH, Rittner CA (1998) Tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 111(3):579–582PubMedCrossRefPubMedCentralGoogle Scholar
  26. Höhler T, Reuss E, Freitag CM, Schneider PM (2005) A functional polymorphism in the IL-10 promoter influences the response after vaccination with HBs Ag and hepatitis A. Hepatology 42(1):72–76PubMedCrossRefGoogle Scholar
  27. Hollegaard MV, Bidwell JL (2006) Cytokine gene polymorphism in human disease: on-line databases, Suppl 3. Genes Immun 7(4):269–276PubMedCrossRefGoogle Scholar
  28. Hurme M, Lahdenpohja N, Santtila S (1998) Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med 30(5):469–473PubMedCrossRefGoogle Scholar
  29. Kew MC (2010) Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma. Pathol Biol (Paris) 58(4):273–277CrossRefGoogle Scholar
  30. Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, Kobayashi T, Shimosegawa T (2006) Mechanism of T cell hiporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B. World J Gastroenterol 12(27):4310–4317PubMedPubMedCentralGoogle Scholar
  31. Koziel MJ (1999) Cytokines in viral hepatitis. Semin Liver Dis 19(2):157–169PubMedCrossRefGoogle Scholar
  32. Kube D, Rieth H, Eskdale J, Kremsner PG, Gallagher G (2001) Structural characterization of the distal 5′ flanking region of the human interleukin-10 gene. Genes Immun 2(4):181–190PubMedCrossRefGoogle Scholar
  33. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y, Wang F, Zheng H, Guo J, Jia Z, Ma J, Wang H, Luo H, Li L, Jin S, Hadler SC, Wang Y (2009) Epidemiological serosurvey of hepatitis B in China: declining HBV prevalence due to hepatitis B vaccination. Vaccine 27(47):6550–6557PubMedCrossRefGoogle Scholar
  34. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS (2004) Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol 72(4):545–550PubMedCrossRefGoogle Scholar
  35. Lu YL, Wu X, Huang HL, Dai LC (2010) Allele polymorphisms of interleukin-10 and hepatitis B, C virus infection. Chin Med J (Engl) 123(10):1338–1344Google Scholar
  36. Miyazoe S, Hamasaki K, Nakata K, Kajiya Y, Kitajima K, Nakao K, Daikoku M, Yatsuhashi H, Koga M, Yano M, Eguchi K (2002) Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus. Am J Gastroenterol 97(8):2086–2092PubMedCrossRefGoogle Scholar
  37. Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165–190PubMedCrossRefGoogle Scholar
  38. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765PubMedCrossRefGoogle Scholar
  39. Mosmann TR (1994) Properties and functions of interleukin-10. Adv Immunol 56:1–26PubMedCrossRefGoogle Scholar
  40. Mullikin JC, Hunt SE, Cole CG, Mortimore BJ, Rice CM, Burton J, Matthews LH, Pavit R, Plumb RW, Sims SK, Ainscough RM, Attwood J, Bailey JM, Barlow K, Bruskiewich RM, Butcher PN, Carter NP, Chen Y, Clee CM, Coggill PC, Davies J, Davies RM, Dawson E, Francis MD, Joy AA, Lamble RG, Langford CF, Macarthy J, Mall V, Moreland A, Overton-Larty EK, Ross MT, Smith LC, Steward CA, Sulston JE, Tinsley EJ, Turney KJ, Willey DL, Wilson GD, McMurray AA, Dunham I, Rogers J, Bentley DR (2000) A single nucleotide polymorphism (SNP) map of human chromosome 22. Nature 407(6803):516–520PubMedCrossRefGoogle Scholar
  41. Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW (1996) Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology 24(4):759–765PubMedCrossRefGoogle Scholar
  42. Payvandi F, Amrute S, Fitzgerald-Bocarsly P (1998) Exogenous and endogenous IL-10 regulate IFN-alpha production by peripheral blood mononuclear cells in response to viral stimulation. J Immunol 160(12):5861–5868PubMedGoogle Scholar
  43. Peng XM, Huang YS, Ma HH, Gu L, Xie QF, Gao ZL (2006) Interleukin-10 promoter polymorphisms are associated with the mode and sequel of HBeAg seroconversion in patients with chronic hepatitis B virus infection. Liver Int 26(3):326–333PubMedCrossRefGoogle Scholar
  44. Perrey C, Pravica V, Sinnott PJ, Hutchinson IV (1998) Genotyping for polymorphisms in interferon-γ, interleukin-10, transforming growth factor-β1 and tumor necrosis factor-α genes: a technical report. Transpl Immunol 6(3):193–197PubMedCrossRefGoogle Scholar
  45. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 22:929–979PubMedCrossRefGoogle Scholar
  46. Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, Shorthouse C, Purdie DM, Jonsson JR (2000) Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 31(4):828–833PubMedCrossRefGoogle Scholar
  47. Redpath S, Ghazal P, Gascoigne NR (2001) Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol 9(2):86–92PubMedCrossRefGoogle Scholar
  48. Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Höhler T (2002) Differential regulation of interleukin-10 production by genetic and environmental factors: a twin study. Genes Immun 3(7):407–413Google Scholar
  49. Shin HD, Park BL, Kim LH, Jung JH, Kim JY, Yoon JH, Kim YJ, Lee HS (2003) Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet 12(8):901–906PubMedCrossRefGoogle Scholar
  50. Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22(15):1928–1929PubMedCrossRefGoogle Scholar
  51. Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL (2010) Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigenpositive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 52(4):1251–1257PubMedCrossRefGoogle Scholar
  52. Spits H, Malefyt RW (1992) Functional characterization of human IL-10. Int Arch Allergy Immunol 99(1):8–15PubMedCrossRefGoogle Scholar
  53. Suárez A, Castro P, Alonso R, Mozo L, Gutiérrez C (2003) Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation 75(5):711–717PubMedCrossRefGoogle Scholar
  54. Thio CL, Carrington M, Marti D, O’Brien SJ, Vlahov D, Nelson KE, Astemborski J, Thomas DL (1999) Class II HLA alleles and hepatitis B virus persistence in African Americans. J Infect Dis 179(4):1004–1006PubMedCrossRefGoogle Scholar
  55. Thio CL, Thomas DL, Carrington M (2000) Chronic viral hepatitis and the human genome. Hepatology 31(4):819–827PubMedCrossRefGoogle Scholar
  56. Thursz M (2001) Genetic susceptibility in chronic viral hepatitis. Antiviral Res 52(3):113–116PubMedCrossRefGoogle Scholar
  57. Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 332(16):1065–1069PubMedCrossRefGoogle Scholar
  58. Tountas NA, Cominelli F (1996) Identification and initial characterisation of two polymorphisms in the human interleukin-10 promoter. Eur Cytokine Netw 7:578Google Scholar
  59. Truelove AL, Oleksyk TK, Shrestha S, Thio CL, Goedert JJ, Donfield SM, Kirk GD, Thomas DL, O’Brien SJ, Smith MW (2008) Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome. Int J Immunogenet 35(3):255–264PubMedCrossRefPubMedCentralGoogle Scholar
  60. Tseng LH, Lin MT, Shau WY, Lin WC, Chang FY, Chien KL, Hansen JA, Chen DS, Chen PJ (2006) Correlation of interleukin-10 gene haplotype with hepatocellular carcinoma in Taiwan. Tissue Antigens 67(2):127–133PubMedCrossRefGoogle Scholar
  61. Tsukamoto H (1998) Is interleukin-10 antifibrogenic in chronic liver injury? Hepatology 28(6):1707–1709PubMedCrossRefGoogle Scholar
  62. Turner DM, William DM, Sankran D, Lazarus M, Sinnott PJ, Hutchinson V (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24(1):1–8PubMedCrossRefGoogle Scholar
  63. Van Deventer SJ (2000) Cytokine and cytokine receptor polymorphisms in infectious disease. Intensive Care Med 26(Suppl 1):S98–S102PubMedCrossRefGoogle Scholar
  64. Velu V, Saravanan S, Nandakumar S, Shankar EM, Vengatesan A, Jadhav SS, Kulkarni PS, Thyagarajan SP (2008) Relationship between T-lymphocyte cytokine levels and sero-response to hepatitis B vaccines. World J Gastroenterol 14(22):3534–3540PubMedCrossRefPubMedCentralGoogle Scholar
  65. Vildózola Gonzales H, Salinas JL (2009) Natural history of chronic hepatitis B virus infection. Rev Gastroenterol Peru 29(2):147–157PubMedGoogle Scholar
  66. Wang C, Zhang X, Zhu B, Hu D, Wu J, Yu R, Zhao W (2012) Relationships between tumour necrosis factor-a, interleukin-12B and interleukin-10 gene polymorphisms and hepatitis B in Chinese Han haemodialysis patients. Nephrology 17(2):167–174PubMedCrossRefGoogle Scholar
  67. Wang S, Huang D, Sun S, Ma W, Zhen Q (2011) Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa. Virol J 8:28PubMedCrossRefPubMedCentralGoogle Scholar
  68. Welsh K, Bunce M (1999) Molecular typing for the MHC with PCR-SSP. Rev Immunogenet 1(2):157–176PubMedGoogle Scholar
  69. Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, Vandenbroucke JP (1997) Genetic influence on cytokine production and fatal meningococcal disease. Lancet 349(9046):170–173PubMedCrossRefGoogle Scholar
  70. Wu JF, Wu TC, Chen CH, Ni YH, Chen HL, Hsu HY, Chang MH (2010) Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion. Gastroenterology 138(1):165–172PubMedCrossRefGoogle Scholar
  71. Wu JF, Ni YH, Lin YT, Lee TJ, Hsu SH, Chen HL, Tsuei DJ, Hsu HY, Chang MH (2011) Human interleukin-10 genotypes are associated with different precore/core gene mutation patterns in children with chronic hepatitis B virus infection. J Pediatr 158(5):808–813PubMedCrossRefGoogle Scholar
  72. Yan Z, Tan W, Zhao W, Dan Y, Wang X, Mao Q, Wang Y, Deng G (2009) Regulatory polymorphisms in the IL-10 gene promoter and HBV-related acute liver failure in the Chinese population. J Viral Hepat 16(11):775–783PubMedCrossRefGoogle Scholar
  73. Yeh SH, Chang CF, Shau WY, Chen YW, Hsu HC, Lee PH, Chen DS, Chen PJ (2002) Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 62(15):4346–4351PubMedGoogle Scholar
  74. Zhang PA, Li Y, Yang XS (2006) Associated study on interleukin 10 gene promoter polymorphisms related to hepatitis B virus infection in Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 23(4):410–414PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Roba M. Talaat
    • 1
  • Mahmoud F. Dondeti
    • 1
  • Soha Z. El-Shenawy
    • 2
  • Omaima A. Khamiss
    • 3
  1. 1.Molecular Biology Department, Genetic Engineering and Biotechnology Research InstituteUniversity of Sadat CitySadat CityEgypt
  2. 2.Biochemistry Department, National Liver InstituteMenofia UniversityMenufiaEgypt
  3. 3.Animal Biotechnology Department, Genetic Engineering and Biotechnology Research InstituteUniversity of Sadat CitySadat CityEgypt

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